Patent Cooperation Treaty ("PCT") patent application no. PCT/US91/02320 filed 3 Apr. 1991, published 17 Oct. 1991, and entitled "An Electronic Technique of Identifying an Effective Drug for Treating a Cancer Patient" discloses a system for monitoring and recording cell cultures. This PCT patent application claims priority from a similarly titled U.S. patent application No. 07/503,791 filed 3 Apr. 1990, now abandoned, that discloses a similar cell culture monitoring and recording system.
The system disclosed in these patent applications monitors and records cells being cultured in a conventional laboratory tray. The tray has a plurality of separate wells with each well being open at one end. This system includes a lid that is disposed on top of the tray to cover the open ends of the tray's wells. Secured to the top surface of the lid is a printed circuit board that has a plurality of individual electrically conductive traces formed on one surface. One end of each trace is adapted to mate with and engage a printed circuit board connector. Also secured to each trace is a non-reactive, stainless steel pin that penetrates both the printed circuit board and the lid. The placement of the traces on the printed circuit board with respect to the lid arranges the pins in pairs so that when the lid is placed on the tray each pair of pins is inserted through the open end of and extends into a different well in the tray.
This system also includes a printed circuit board connector that mates with the traces of the printed circuit board and through which one pin of every pair is electrically connected to a common potential. An electronic data acquisition board is electrically coupled to the printed circuit board connector. The electronic data acquisition board includes a voltage source for applying an electrical voltage across a pair of the pins. A plurality of well switches, also included in the electronic data acquisition board, selects one particular pair of the pins to receive the voltage supplied by the voltage source. In operation, the electronic data acquisition board preferably applies an alternating current voltage of approximately 10 millivolts peak-to-peak across the pair of pins. This alternating current voltage preferably has a frequency of approximately 400 Hz that is not harmonically related to 60 Hz. An amplifier, also included in the electronic data acquisition board, has an input that receives the voltage applied across the pair of pins selected by the well switches. From its output, the amplifier transmits a signal that responds to the voltage present at the amplifier's input to a sample-and-hold circuit. The sample-and-hold circuit receives the output signal from the amplifier and, in turn, transmits a signal responsive to that signal.
This cell culture monitoring and recording system also includes a computer system that itself includes a measurement input/output circuit. The measurement input/output circuit includes means for supplying signals to the electronic data acquisition board for specifying a particular pair of pins to be selected by the switches. The measurement input/output circuit also includes an analog-to-digital converter that receives and digitizes the signal from the sample-and-hold amplifier to produce a digital number. For processing these digital numbers, the computer system includes a means for storing them as raw data, and means for analyzing the raw data and graphically displaying the results of such analysis.
While the system disclosed in these patent applications is capable of monitoring and recording cells during culture, certain limitations render the precise embodiment disclosed in the patent applications unsuitable for widespread commercial application. For example, pins made from electrically conductive, non-reactive stainless steel do not always achieve a reliable electrical connection to the traces of the printed circuit board. Thus, occasionally, one or more pairs of pins out of all the pairs in a lid might produce an erratic reading, or no reading at all. Such an intermittent or open circuit condition might occur several hours or days into a test monitoring and recording cell growth, thereby severely reducing or perhaps destroying the usefulness of the test results. Similarly, drift in the electronic components used in the system over several days of a test could introduce instability and/or inaccuracy into measurements recorded by the system. Furthermore, during culture cells may be damaged and/or destroyed if a monitoring system inadvertently applies a voltage, that while being very small, is still excessively large in comparison with biological electrical potentials. Also, the data analysis techniques disclosed in the patent applications identified above did not most effectively reveal the full quality of data obtained with the system.